| Structural highlights
Function
C1QBP_HUMAN Is believed to be a multifunctional and multicompartmental protein involved in inflammation and infection processes, ribosome biogenesis, regulation of apoptosis, transcriptional regulation and pre-mRNA splicing. At the cell surface is thought to act as an endothelial receptor for plasma proteins of the complement and kallikrein-kinin cascades. Putative receptor for C1q; specifically binds to the globular "heads" of C1q thus inhibiting C1; may perform the receptor function through a complex with C1qR/CD93. In complex with cytokeratin-1/KRT1 is a high affinty receptor for kininogen-1/HMWK. Can also bind other plasma proteins, such as coagulation factor XII leading to its autoactivation. May function to bind initially fluid kininogen-1 to the cell membrane. The secreted form may enhance both extrinsic and intrinsic coagulation pathways. It is postulated that the cell surface form requires docking with transmembrane proteins for downstream signaling which might be specific for a cell-type or response. By acting as C1q receptor is involved in chemotaxis of immature dendritic cells and neutrophils and is proposed to signal through CD209/DC-SIGN on immature dendritic cells, through integrin alpha-4/beta-1 during trophoblast invasion of the decidua, and through integrin beta-1 during endothelial cell adhesion and spreading. Signaling involved in inhibition of innate immune response is implicating the PI3K-AKT/PKB pathway. In mitochondrial translation may be involved in formation of functional 55S mitoribosomes; the function seems to involve its RNA-binding activity. May be involved in the nucleolar ribosome maturation process; the function may involve the exchange of FBL for RRP1 in the association with pre-ribosome particles. Involved in regulation of RNA splicing by inhibiting the RNA-binding capacity of SRSF1 and its phosphorylation. Is required for the nuclear translocation of splicing factor U2AF1L4. Involved in regulation of CDKN2A- and HRK-mediated apoptosis. Stabilizes mitochondrial CDKN2A isoform smARF. May be involved in regulation of FOXC1 transcriptional activity and NFY/CCAAT-binding factor complex-mediated transcription. In infection processes acts as an attachment site for microbial proteins, including Listeria monocytogenes internalin B and Staphylococcus aureus protein A. May play a role in antibacterial defense as it can bind to cell surface hyaluronan and inhibit Streptococcus pneumoniae hyaluronate lyase. Involved in replication of Rubella virus. May be involved in modulation of the immune response; ligation by HCV core protein is resulting in suppresion of interleukin-12 production in monocyte-derived dendritic cells. Involved in regulation of antiviral response by inhibiting DDX58- and IFIH1-mediated signaling pathways probably involving its association with MAVS after viral infection. Involved in HIV-1 replication, presumably by contributing to splicing of viral RNA.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]
Publication Abstract from PubMed
The contact system is composed of Factor XII (FXII), prekallikrein (PK) and co-factor kininogen (HK). The globular C1q receptor (gC1qR) has been shown to interact with FXII and HK. We reveal the FXII fibronectin type II domain (FnII) binds gC1qR in a Zn2+ dependent fashion and determined the complex crystal structure. FXIIFnII binds the gC1qR trimer in an asymmetric fashion with residues Arg36 and Arg65 forming contacts with two distinct negatively charged pockets. gC1qR residues Asp185 and His187 coordinate a Zn2+ adjacent to the FXII binding site and a comparison with the ligand free gC1qR crystal structure reveals the anionic G1-loop becomes ordered upon FXIIFnII binding. Additional conformational changes in the region of the Zn2+ binding site reveal an allosteric basis for Zn2+ modulation of FXII binding. Mutagenesis coupled with SPR demonstrate the gC1qR Zn2+ site contributes to FXII binding and plasma based assays reveal gC1qR stimulates coagulation in a FXII-dependent manner. Analysis of the binding of HK domain 5 (HKD5) to gC1qR shows only one high affinity binding site per trimer. Mutagenesis studies identify a critical G3-loop located at the center of the gC1qR trimer suggesting steric occlusion as the mechanism for HKD5 asymmetric binding. Gel filtration experiments reveal that gC1qR clusters FXII and HK into a higher order 500kDa ternary complex. These results support the conclusion that extracellular gC1qR can act as a chaperone to cluster contact factors which may be a prelude for initiating the cascades which drive bradykinin generation and the intrinsic pathway of coagulation.
Factor XII and kininogen asymmetric assembly with gC1qR/C1QBP/P32 is governed by allostery.,Kaira BG, Slater A, McCrae KR, Dreveny I, Sumya UM, Mutch NJ, Searle M, Emsley J Blood. 2020 Jun 19. pii: 461064. doi: 10.1182/blood.2020004818. PMID:32559765[22]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Herwald H, Dedio J, Kellner R, Loos M, Muller-Esterl W. Isolation and characterization of the kininogen-binding protein p33 from endothelial cells. Identity with the gC1q receptor. J Biol Chem. 1996 May 31;271(22):13040-7. PMID:8662673
- ↑ Joseph K, Ghebrehiwet B, Peerschke EI, Reid KB, Kaplan AP. Identification of the zinc-dependent endothelial cell binding protein for high molecular weight kininogen and factor XII: identity with the receptor that binds to the globular "heads" of C1q (gC1q-R). Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8552-7. PMID:8710908
- ↑ Leigh LE, Ghebrehiwet B, Perera TP, Bird IN, Strong P, Kishore U, Reid KB, Eggleton P. C1q-mediated chemotaxis by human neutrophils: involvement of gClqR and G-protein signalling mechanisms. Biochem J. 1998 Feb 15;330 ( Pt 1):247-54. PMID:9461517
- ↑ Joseph K, Ghebrehiwet B, Kaplan AP. Cytokeratin 1 and gC1qR mediate high molecular weight kininogen binding to endothelial cells. Clin Immunol. 1999 Sep;92(3):246-55. PMID:10479529 doi:10.1006/clim.1999.4753
- ↑ Petersen-Mahrt SK, Estmer C, Ohrmalm C, Matthews DA, Russell WC, Akusjarvi G. The splicing factor-associated protein, p32, regulates RNA splicing by inhibiting ASF/SF2 RNA binding and phosphorylation. EMBO J. 1999 Feb 15;18(4):1014-24. PMID:10022843 doi:10.1093/emboj/18.4.1014
- ↑ Braun L, Ghebrehiwet B, Cossart P. gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogenes. EMBO J. 2000 Apr 3;19(7):1458-66. PMID:10747014 doi:10.1093/emboj/19.7.1458
- ↑ Nguyen T, Ghebrehiwet B, Peerschke EI. Staphylococcus aureus protein A recognizes platelet gC1qR/p33: a novel mechanism for staphylococcal interactions with platelets. Infect Immun. 2000 Apr;68(4):2061-8. PMID:10722602
- ↑ Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, Braciale TJ, Hahn YS. Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation. J Clin Invest. 2000 Nov;106(10):1239-49. PMID:11086025 doi:10.1172/JCI10323
- ↑ Feng X, Tonnesen MG, Peerschke EI, Ghebrehiwet B. Cooperation of C1q receptors and integrins in C1q-mediated endothelial cell adhesion and spreading. J Immunol. 2002 Mar 1;168(5):2441-8. PMID:11859136
- ↑ Zheng YH, Yu HF, Peterlin BM. Human p32 protein relieves a post-transcriptional block to HIV replication in murine cells. Nat Cell Biol. 2003 Jul;5(7):611-8. PMID:12833064 doi:10.1038/ncb1000
- ↑ Chattopadhyay C, Hawke D, Kobayashi R, Maity SN. Human p32, interacts with B subunit of the CCAAT-binding factor, CBF/NF-Y, and inhibits CBF-mediated transcription activation in vitro. Nucleic Acids Res. 2004 Jul 8;32(12):3632-41. Print 2004. PMID:15243141 doi:10.1093/nar/gkh692
- ↑ Waggoner SN, Cruise MW, Kassel R, Hahn YS. gC1q receptor ligation selectively down-regulates human IL-12 production through activation of the phosphoinositide 3-kinase pathway. J Immunol. 2005 Oct 1;175(7):4706-14. PMID:16177118
- ↑ Vegh Z, Kew RR, Gruber BL, Ghebrehiwet B. Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR. Mol Immunol. 2006 Mar;43(9):1402-7. Epub 2005 Sep 2. PMID:16140380 doi:10.1016/j.molimm.2005.07.030
- ↑ Waggoner SN, Hall CH, Hahn YS. HCV core protein interaction with gC1q receptor inhibits Th1 differentiation of CD4+ T cells via suppression of dendritic cell IL-12 production. J Leukoc Biol. 2007 Dec;82(6):1407-19. Epub 2007 Sep 19. PMID:17881511 doi:10.1189/jlb.0507268
- ↑ Huang L, Chi J, Berry FB, Footz TK, Sharp MW, Walter MA. Human p32 is a novel FOXC1-interacting protein that regulates FOXC1 transcriptional activity in ocular cells. Invest Ophthalmol Vis Sci. 2008 Dec;49(12):5243-9. doi: 10.1167/iovs.07-1625., Epub 2008 Aug 1. PMID:18676636 doi:10.1167/iovs.07-1625
- ↑ Yadav G, Prasad RL, Jha BK, Rai V, Bhakuni V, Datta K. Evidence for inhibitory interaction of hyaluronan-binding protein 1 (HABP1/p32/gC1qR) with Streptococcus pneumoniae hyaluronidase. J Biol Chem. 2009 Feb 6;284(6):3897-905. doi: 10.1074/jbc.M804246200. Epub 2008, Nov 11. PMID:19004836 doi:10.1074/jbc.M804246200
- ↑ Xu L, Xiao N, Liu F, Ren H, Gu J. Inhibition of RIG-I and MDA5-dependent antiviral response by gC1qR at mitochondria. Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1530-5. doi: 10.1073/pnas.0811029106., Epub 2009 Jan 21. PMID:19164550 doi:10.1073/pnas.0811029106
- ↑ Agostinis C, Bulla R, Tripodo C, Gismondi A, Stabile H, Bossi F, Guarnotta C, Garlanda C, De Seta F, Spessotto P, Santoni A, Ghebrehiwet B, Girardi G, Tedesco F. An alternative role of C1q in cell migration and tissue remodeling: contribution to trophoblast invasion and placental development. J Immunol. 2010 Oct 1;185(7):4420-9. doi: 10.4049/jimmunol.0903215. Epub 2010 Sep, 1. PMID:20810993 doi:10.4049/jimmunol.0903215
- ↑ Yoshikawa H, Komatsu W, Hayano T, Miura Y, Homma K, Izumikawa K, Ishikawa H, Miyazawa N, Tachikawa H, Yamauchi Y, Isobe T, Takahashi N. Splicing factor 2-associated protein p32 participates in ribosome biogenesis by regulating the binding of Nop52 and fibrillarin to preribosome particles. Mol Cell Proteomics. 2011 Aug;10(8):M110.006148. doi: 10.1074/mcp.M110.006148., Epub 2011 May 2. PMID:21536856 doi:10.1074/mcp.M110.006148
- ↑ Pixley RA, Espinola RG, Ghebrehiwet B, Joseph K, Kao A, Bdeir K, Cines DB, Colman RW. Interaction of high-molecular-weight kininogen with endothelial cell binding proteins suPAR, gC1qR and cytokeratin 1 determined by surface plasmon resonance (BiaCore). Thromb Haemost. 2011 Jun;105(6):1053-9. doi: 10.1160/TH10-09-0591. Epub 2011 May , 5. PMID:21544310 doi:10.1160/TH10-09-0591
- ↑ Hosszu KK, Valentino A, Vinayagasundaram U, Vinayagasundaram R, Joyce MG, Ji Y, Peerschke EI, Ghebrehiwet B. DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on the surface of monocyte-derived immature dendritic cells. Blood. 2012 Aug 9;120(6):1228-36. doi: 10.1182/blood-2011-07-369728. Epub 2012, Jun 13. PMID:22700724 doi:10.1182/blood-2011-07-369728
- ↑ Kaira BG, Slater A, McCrae KR, Dreveny I, Sumya U, Mutch NJ, Searle M, Emsley J. Factor XII and kininogen asymmetric assembly with gC1qR/C1QBP/P32 is governed by allostery. Blood. 2020 Oct 1;136(14):1685-1697. PMID:32559765 doi:10.1182/blood.2020004818
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